Cisplatin, 5-fluorouracil, and cetuximab (PFE) with or without cilengitide in recurrent/metastatic squamous cell carcinoma of the head and neck: results of the randomized phase I/II ADVANTAGE trial (phase II part).

BACKGROUND: Recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M-SCCHN) overexpresses αvß5 integrin. Cilengitide selectively inhibits αvß3 and αvß5 integrins and is investigated as a treatment strategy. PATIENTS AND METHODS: The phase I/II study ADVANTAGE evaluated cilengitide combined with cisplatin, 5-fluorouracil, and cetuximab (PFE) in R/M-SCCHN. The phase II part reported here was an open-label, randomized, controlled trial investigating progression-free survival (PFS). Patients received up to six cycles of PFE alone or combined with cilengitide 2000 mg once (CIL1W) or twice (CIL2W) weekly. Thereafter, patients received maintenance therapy (cilengitide arms: cilengitide plus cetuximab; PFE-alone arm: cetuximab only) until disease progression or unacceptable toxicity. RESULTS: One hundred and eighty-two patients were treated. Median PFS per investigator read was similar for CIL1W + PFE, CIL2W + PFE, and PFE alone (6.4, 5.6, and 5.7 months, respectively). Accordingly, median overall survival and objective response rates were not improved with cilengitide (12.4 months/47%, 10.6 months/27%, and 11.6 months/36%, respectively). No clinically meaningful safety differences were observed between groups. None of the tested biomarkers (expression of integrins, CD31, Ki-67, vascular endothelial growth factor receptor 2, vascular endothelial-cadherin, type IV collagen, epidermal growth factor receptor, or p16 for human papillomavirus) were predictive of outcome. CONCLUSION: Neither of the cilengitide-containing regimens demonstrated a PFS benefit over PFE alone in R/M-SCCHN patients.

Phase 2, open-label, 1:1 randomized controlled trial exploring the efficacy of EMD 1201081 in combination with cetuximab in second-line cetuximab-naïve patients with recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN).

AIM: To determine whether EMD 1201081, a TLR9 agonist, added to cetuximab had antitumor activity in second-line recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). METHODS: This was a phase 2, open-label, randomized trial of EMD 1201081 0.32 mg/kg subcutaneously weekly plus cetuximab (combination) vs cetuximab monotherapy (control) in cetuximab-naïve patients with R/M SCCHN who progressed on 1 cytotoxic regimen. Crossover to combination was permitted after progression. RESULTS: Objective response rate in both arms was 5.7% (95% CI 1.2-15.7%) by independent assessment. Disease control was 37.7% for patients on combination (24.8-52.1%) and 43.4% on control (29.8-57.7%). Neither independent nor investigator assessments showed significant differences between study arms. Median progression-free survival was 1.5 months (1.3-2.6) for patients on combination, and 1.9 months (1.5-2.9) on control. The most frequent adverse events in the combination arm were rash (29.6%), acneiform dermatitis (22.2%), and injection site reactions (20.4%). Grade 3/4 dyspnea and hypokalemia were more frequent with cetuximab monotherapy (7.5% and 5.7% vs 1.9% each, respectively), and grade 3/4 respiratory failure and disease progression were more frequent with combination (5.6% each vs 1.9% each). CONCLUSION: EMD 1201081 was well tolerated combined with cetuximab, but there was no incremental clinical efficacy.

Evaluation of EGFR gene copy number as a predictive biomarker for the efficacy of cetuximab in combination with chemotherapy in the first-line treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck: EXTREME study.

BACKGROUND: The phase III EXTREME study demonstrated that combining cetuximab with platinum/5-fluorouracil (5-FU) significantly improved overall survival in the first-line treatment of patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) compared with platinum/5-FU alone. The aim of this investigation was to evaluate elevated tumor EGFR gene copy number as a predictive biomarker in EXTREME study patients. PATIENTS AND METHODS: Dual-color FISH was used to determine absolute and relative EGFR copy number. Models of differing stringencies were used to score and investigate whether increased copy number was predictive for the activity of cetuximab plus platinum/5-FU. RESULTS: Tumors from 312 of 442 patients (71%) were evaluable by FISH and met the criteria for statistical analysis. A moderate increase in EGFR copy number was common, with high-level amplification of the gene occurring in a small fraction of tumors (∼11%). Considering each of the models tested, no association of EGFR copy number with overall survival, progression-free survival or best overall response was found for patients treated with cetuximab plus platinum/5-FU. CONCLUSION: Tumor EGFR copy number is not a predictive biomarker for the efficacy of cetuximab plus platinum/5-FU as first-line therapy for patients with R/M SCCHN.

Effects of free fatty acids on meibomian lipid films.

The purpose of this study was to evaluate the impact of free fatty acids (FFA), namely oleic (OA) and linoleic (LA) ones, on meibomian lipid films (MLF) using a Langmuir trough (LT) and a Brewster angle microscope (BAM). Human meibum was collected from healthy volunteers. A Tris-buffered saline (TBS, pH 7.4) was used as the control aqueous subphase for LT experiments. Then, varying amounts of OA and LA were dissolved in TBS to make FFA-containing subphases. Predetermined amounts of meibum were loaded onto the surface of the (TBS/±FFA) subphases to form MLF. Then, surface pressure-area (π/A) isotherms of MLF were recorded. Standard rheological parameters such as rigidity, elasticity, and hysteresis, were computed. In a separate experiment, OA and LA were pre-mixed with meibum at different weight ratios prior their spreading onto the control TBS subphase, and the (π/A) isotherms of the resulting mixed films of meibum and FFA were studied and analyzed in the same fashion as described above. When studied at the normal corneal temperature of 34 °C with the (TBS/-FFA) subphase, meibum formed stable films. When (TBS/+FFA) subphase was used, both FFA quickly disrupted the MLF, acting in a similar fashion. BAM revealed that the most dramatic changes in the structure of MLF occurred in the range of OA concentrations between 5 and 15 µM. However, this effect was apparent even with 2.5 µM OA. When OA was pre-mixed with meibum, but was absent from the subphase, it caused gradual concentration-dependent changes in the (π/A) isotherms, but the MLF did not disappear from the surface. Thus, tested FFA showed a remarkable ability to disrupt, and/or prevent the formation of, human MLF, which could contribute to the onset of those forms of dry eye disease that are associated with enhanced activity of lipolytic enzymes, such as chronic blepharitis.

Prognostic value of dynamic renal scan with 99mTc-EC in patients with kidney transplantation: a prospective descriptive study.

INTRODUCTION: Renal transplantation is the gold standard treatment for chronic kidney disease. Renal scintigraphy has been performed widely to evaluate postsurgical complications of transplantation, but there are little data regarding 99mTc-EC scintigraphy in kidney transplantation. METHODS AND MATERIALS: This was a prospective descriptive study. All patients who underwent kidney transplantation and passed an uneventful postoperative period entered the study. Demographic characteristics, including age, gender, biochemical parameters before and after the transplantation and 99mTc-EC parameters including time to max, time to ½ max, slope from max to ½ max, upslope time interval and time to 2/3 max as well as episodes of rejection, were recorded. Patients were then followed up for 1 year at 3-, 6-, 9- and 12-month intervals. RESULTS: Forty-one patients who underwent renal transplantation entered the study. Mean ± SD age of patients was 40.65 ± 12.84 years (min 17 and max 74 years). In total, 25% (10) of patients experienced one or two episodes of rejection and were hospitalized. Time of max, time of 1/2 max, time from max to 1/2 max, time of 2/3 max, time from max to 2/3 max and upslope time interval had a significant association with transplant rejection using a Cox regression model. With 1-min increase in time of max, the risk of rejection increased by 27% (hazard ratio = 1.27; CI, 1.03--1.56) and with 1-min increase in time of 1/2 max, the risk of rejection increased by 28% (hazard ratio = 1.28; CI, 1.14-1.45). DISCUSSION: 99mTc-EC renal scintigrahpy was able to predict kidney transplantation rejection in our patients. 99mTc-EC renal scintigrahpy is beneficial to evaluate transplant kidney function to prevent complications and helps close follow-up.

[Quality assurance, audit and quality control of radiotherapy at radiology departments in Hungary]. / A magyarországi sugárterápiás osztályok minöségbiztosítási, számvetési és minöségellenörzési rendszere.

The first quality assurance, audit and control system in the Hungarian "'health" care industry" is described for the medical specialty of radiotherapy. The prerequisites of the elaboration of the programme were an exact knowledge of the current Hungarian infrastructural and staffing conditions, and the radiotherapeutic activities. The recommendations cover the 5 medical universities including the national institute (the Debrecen, Pécs, Semmelweis, Szent-Györgyk Albert Medical Universities, and Haynal Imre University of Health Sciences) and the 5 regional oncological centres in hospitals (Jósa András, Markusovszky, Petz Aladár, Szentpéteri kapu and Uzsoki Hospitals). The departmental functions (patient care, teaching-education, research work and scientific organizing activity) and the structure (organization, infrastructure, staffing conditions, etc.) are described first, followed by the therapeutic principles and clinical process (patient referral and selection, decision-making, priorities in therapy initiation, treatment preparation and execution, etc.). The informal daily/weekly quality assurance programme long applied in the routine patient care has been formalized and supplemented with a weekly audit conference. In the course of the medical audit, all relevant clinical data are reviewed and scored by an internal or an external expert (not participating directly in the treatment process), e.g. for the adequacy of the medical decision preparative process, conformation to the institutional treatment protocol, equipment selection, treatment planning, simulation and portal film, etc. If a major deviation is detected, an immediate correction is initiated; minor deviations need analysis and then preventive and correcting action. As concern the audit of the other activities of the departments, the important indicators and their minimally desirable level are defined. The final goal of the implementation of this programme is high-precision radiotherapy with the best achievable treatment result.